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Specific Deficiency of p56^lck Expression in T Lymphocytes from Type 1 Diabetic Patients¹

Solange Nervi^*, Catherine Atlan-Gepner^*, Brigitte Kahn-Perles, Patrick Lecine, Bernard Vialettes^*, Jean Imbert and Philippe Naquet^2,

^* UPRES-EA2193, Institut Fédiratif de Recherche 35, Physiopathologie Métabolique et Nutritionnelle, Université de la Méditerranée, Centre Hospitalier Universitaire Timone, Marseille, France; and Institut National de la Santé et de la Recherche Médicale Unité 119, Institut Fédiratif de Recherche 57, and Centre d’Immunologie, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique de Marseille-Luminy, Institut Fédiratif de Recherche 57, Institute of Immunology and Cancer, Marseille, France

Peripheral T lymphocyte activation in response to TCR/CD3 stimulation is reduced in type 1 diabetic patients. To explore the basis of this deficiency, a comprehensive analysis of the signal transduction pathway downstream of the TCR/CD3 complex was performed for a cohort of patients (n = 38). The main result of the study shows that T cell hyporesponsiveness is positively correlated with a reduced amount of p56^lck in resting T lymphocytes. Upon CD3-mediated activation, this defect leads to a hypophosphorylation of the CD3-chain and few other polypeptides without affecting the recruitment of ZAP70. Other downstream effectors of the TCR/CD3 transduction machinery, such as phosphatidylinositol 3-kinase p85, p59^fyn, linker for activation of T cells (LAT), and phospholipase C-1, are not affected. In some patients, the severity of this phenotypic deficit could be linked to low levels of p56^lck mRNA and resulted in the failure to efficiently induce the expression of the CD69 early activation marker. We propose that a primary deficiency in human type 1 diabetes is a defect in TCR/CD3-mediated T cell activation due to the abnormal expression of the p56^lck tyrosine kinase.

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